It has been proposed that rapid disease in human immunodeficiency virus (HIV) -infected infants may be due to transmission of highly pathogenic maternal virus strains. It is also possible that mucosal surfaces may restrict perinatal transmission of some viral variants and so alter disease course in HIV-infected children. We evaluated newborn rhesus macaques inoculated with one of three simian immunodeficiency virus (SIV) variants, whose virulence was assessed previously in juvenile and adult animals. An uncloned isolate, SIVmac251, and the molecularly cloned virus, SIVmac239, both produce a persistent infection and cause fatal immunodeficiency disease similar to AIDS in juvenile and adult rhesus macaques. In contrast, infection of older rhesus with virus from the molecular clone SIVmac1A11 produces a transient, cell-associated viremia and no disease. We tested the hypothesis that disease pathogenesis in SIV-infected neonatal rhesus macaques can be modulated by two factors (1) the virulence of the SIV isolate, and (2) the route (parenteral or mucosal) of virus exposure. Five neonates inoculated intravenously (IV) with SIVmac251 showed persistently high viremia, poor weight gain, and rapidly fatal immunodeficiency. Oral inoculation of neonates with SIVmac251 produced rapidly fatal disease in three of four neonates with levels of viremia similar to IV-inoculated animals. Two SIVmac239-infected neonates had a slower disease course despite persistently high viremia. In contrast, SIVmac1A11 was non-pathogenic in neonates. Three neonates inoculated IV with SIVmac1A11 all became infected; however, virus was recovered from only one of four neonates following oral inoculation. All SIVmac1A11-infected neonates had a transient, low-level viremia, normal weight gain, and no clinical disease during more than nine months after infection. Thus, virus-specific factors, but not the route of virus exposure, account for the differences in virulence observed for these SIV variants in rhesus neonates. *KEY* Pediatric simian AIDS, Oral SIV transmission, Perinatal HIV transmission